Macrolide resistance in pneumococci—is it relevant?
© The Author(s) 2016
Received: 5 January 2015
Accepted: 16 June 2016
Published: 7 July 2016
Macrolide antibiotics are widely used for a range of indications, including pneumonia. Both high-level and low-level resistance to macrolides is increasing in pneumococci globally. Macrolide resistance in pneumococci is of limited clinical relevance where ß-lactams remain the mainstay of treatment, such as for moderate/severe pneumonia; however, data suggest that macrolides may not be able to be relied on as monotherapy for serious pneumococcal infections.
KeywordsStreptococcus pneumoniae Antibiotic resistance Macrolides Community-acquired pneumonia
Macrolide antibiotics, including clarithromycin and azithromycin, remain an important class of antimicrobials for pneumococcal diseases. In Australia, azithromycin is recommended in combination with ceftriaxone as empiric therapy for severe pneumonia, and clarithromycin is a second line therapy for mild/moderate community-acquired pneumonia. United States (US) guidelines are currently being revised, but current recommendations list macrolides as monotherapy for outpatient pneumonia, and macrolides in combination with ß-lactams for more severe pneumonia . Although antibiotics are not routinely recommended for otitis media, there is an exception for high-risk children with otitis media (with or without perforation), in which case azithromycin is listed as one of several therapeutic options . However, the main selection pressure for resistant pneumococci may come from its use in other indications such as for non-pneumococcal respiratory tract infection , bronchiectasis and chronic obstructive pulmonary disease (COPD) , sexually transmitted diseases and trachoma  (in different settings).
The increasing prevalence of macrolide-resistant pneumococci has raised concerns about its place in therapy. There are two major mechanisms mediating resistance to macrolides. The ermB gene encodes a methyltransferase that causes ribosomal methylation, resulting in the macrolide-lincosamide-streptogramin B (MLSB) phenotype that reduces susceptibility to macrolides, lincosamide, and streptogramin B. This may be expressed in a constitutive or inducible fashion . mefA codes for an antibiotic efflux pump removing the drug from the target site. ermB tends to confer high level resistance to macrolides with MICs >64 mg/l, whereas the efflux mechanism results in lower MICs for erythromycin (typically in the 1–16 mg/l range), compared to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint for erythromycin (and clarithromycin and azithromycin) of 0.25 mg/l. Other resistance mechanisms also exist, including the mefE variant efflux pump carried on the macrolide efflux genetic assembly (mega), mutations in 23S rRNA and also in the L4 and L22 proteins, and the rare ermA methyltransferase .
There are significant global differences in susceptibility and the mechanisms of resistance. The highest rates of resistance have been reported in East Asia (particularly China, Japan, and South Korea) [8–10] and rapid increases in resistance are occurring in Malaysia . Globally, ermB methyltransferase is more common, but the proportion of isolates carrying this gene was higher in several European countries, and less common in North America . Co-existence of both ermB and mefA is relatively common in some settings. It has been reported at 15 % in South Africa , but as high as 38 % in Russia and nearly 50 % in Vietnam .
Because of the association between resistance and pneumococcal serotypes, conjugate pneumococcal vaccination has impacted on the epidemiology of resistance. In some places the 7-valent vaccine has been shown to cause a significant and lasting decline in macrolide resistance through reduction in carriage and disease due to serotypes 6B, 9 V, 19 F and 23 F that can carry the erm or mef genes [14, 15]. While the concerns about replacement with drug-resistant non-vaccine serotypes such as 19A have mostly been addressed by the 13-valent vaccine, replacement with other non-vaccine serotypes and capsular transformation remains a concern [16–19].
Newer macrolides are concentrated intracellularly, and this is thought to result in increased drug delivery to the site of infection, and exposure to high concentrations of drug following phagocytosis, which may overcome low level resistance . However, it has been suggested that high-level resistance may be clinically relevant . A case control study found that 24 % of patients with erythromycin-resistant pneumococcal bacteraemia were taking a macrolide at the time of bacteraemia, compared to none of 136 matched controls with erythromycin-sensitive pneumococcal bacteraemia .
The concern about resistance is mitigated by the clinical use of this antibiotic class. There are few indications for macrolide monotherapy for pneumococcal disease. Macrolide monotherapy still has a place in the treatment of community-acquired pneumonia in patients who are allergic to ß-lactams. A meta-analysis compared clinical outcomes in trials involving macrolides, stratified by resistance to azithromycin . Curiously, only 5 of the 13 trials involved community-acquired pneumonia, and the remainder arguably involved patients in whom antibiotics are not indicated, such as chronic bronchitis, acute bacterial sinusitis, and acute otitis media. Although, overall a difference in clinical cure was seen in patients with azithromycin resistance (89.4 % vs. 78.6 %, p = 0.003), no differences were evident in patients with pneumonia (94.2 % vs. 92.6 %, p = 0.63). Additionally, clinical failure rates across all trials were similar in patients with low-level resistance (77.5 %) compared to high-level resistance (79.2 %).
Another specific indication for macrolides is otitis media in high-risk groups, such as Australian Indigenous children. A clinical trial performed in a setting where resistance was relatively uncommon suggests that clinical outcomes of single dose azithromycin are similar to a 7-day course of amoxicillin, as well as reducing nasal pneumococcal carriage . However, a higher proportion of the children on azithromycin that did carry pneumococci had resistance (10 % vs. 3 %, p = 0.001), suggesting that resistance may attenuate this benefit over time.
There are also a number of reasons for the use of macrolides other than their effect on bacteria. There has long been interest in the anti-inflammatory effects of macrolides, and a major indication for its use is in bronchiectasis particularly associated with cystic fibrosis [25, 26]. A 2004 observational study found a large and significance difference in mortality between patients treated with a macrolide-based combination of antibiotics compared with those on monotherapy . Studies have since found a difference in mortality (to a smaller degree) in pneumococcal pneumonia [28, 29]. This difference may possibly be explained by a lower severity of infection associated with macrolide-resistant pneumococci .
Clinical trials adding a macrolide to ß-lactams have not definitively demonstrated clinical benefit, but have tested adjunctive macrolides for community-acquired pneumonia generally, rather than pneumococcal pneumonia specifically. One trial found a shorter time to clinical stability in patients with severe pneumonia although the difference in this small trial was not statistically significant . Additionally, there were no differences in other groups or outcomes including length of stay or mortality. A recent cluster randomised trial did not find any differences in mortality or hospital length of stay . The place of adjunctive macrolide therapy in pneumococcal pneumonia remains uncertain.
In summary, macrolide resistance in pneumococci is of limited clinical relevance where ß-lactams remain the mainstay of treatment. However, data suggest that macrolides may not be able to be relied on as monotherapy for serious pneumococcal infections.
COPD, chronic obstructive pulmonary disease; MLSB, macrolide-lincosamide-streptogramin B; MIC, minimum inhibitory concentration; EUCAST, European Committee on Antimicrobial Susceptibility Testing
AC is supported by a NHMRC Career Development Fellowship.
Availability of data and materials
AC and AJ drafted the themes, reviewed the literature, wrote the manuscript and critically reviewed the manuscript for important intellectual content. Both authors read and approved the final manuscript.
AC is a member of the ‘Therapeutic Guidelines: Antibiotic’ writing group.
Consent for publication
Ethics approval and consent to participate
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44 Suppl 2:S27–72. PMID:17278083 http://dx.doi.org/10.1086/511159.View ArticlePubMedGoogle Scholar
- Darwin Otitis Guidelines Group. Recommendations for clinical care guidelines on the management of otitis media in Aboriginal and Torres Strait Islander populations. Canberra: OATSIH; 2010.
- Suda KJ, Hicks LA, Roberts RM, Hunkler RJ, Taylor TH. Trends and seasonal variation in outpatient antibiotic prescription rates in the United States, 2006 to 2010. Antimicrob Agents Chemother. 2014;58:2763–6. PMID:24590486, http://dx.doi.org/10.1128/AAC.02239-13.View ArticlePubMedPubMed CentralGoogle Scholar
- Hare KM, Singleton RJ, Grimwood K, Valery PC, Cheng AC, Morris PS, et al. Longitudinal nasopharyngeal carriage and antibiotic resistance of respiratory bacteria in indigenous Australian and Alaska native children with bronchiectasis. PLoS ONE. 2013;8:e70478. PMID:23940582, http://dx.doi.org/10.1371/journal.pone.0070478.View ArticlePubMedPubMed CentralGoogle Scholar
- Keenan JD, Klugman KP, McGee L, Vidal JE, Chochua S, Hawkins P, et al. Evidence for clonal expansion after antibiotic selection pressure: pneumococcal multilocus sequence types before and after mass azithromycin treatments. J Infect Dis. 2015;211:988–94. PMID:25293366, http://dx.doi.org/10.1093/infdis/jiu552.View ArticlePubMedGoogle Scholar
- Liñares J, Ardanuy C, Pallares R, Fenoll A. Changes in antimicrobial resistance, serotypes and genotypes in Streptococcus pneumoniae over a 30-year period. Clin Microbiol Infect. 2010;16:402–10. PMID:20132251, http://dx.doi.org/10.1111/j.1469-0691.2010.03182.x.View ArticlePubMedGoogle Scholar
- Reinert RR. The antimicrobial resistance profile of Streptococcus pneumoniae. Clin Microbiol Infect. 2009;15 Suppl 3:7–11. PMID:19366363, http://dx.doi.org/10.1111/j.1469-0691.2009.02724.x.View ArticlePubMedGoogle Scholar
- Song JH, Jung SI, Ko KS, Kim NY, Son JS, Chang HH, et al. High prevalence of antimicrobial resistance among clinical Streptococcus pneumoniae isolates in Asia (an ANSORP study). Antimicrob Agents Chemother. 2004;48:2101–7. PMID:15155207, http://dx.doi.org/10.1128/AAC.48.6.2101-2107.2004.View ArticlePubMedPubMed CentralGoogle Scholar
- Song JH, Chang HH, Suh JY, Ko KS, Jung SI, Oh WS, et al. Macrolide resistance and genotypic characterization of Streptococcus pneumoniae in Asian countries: a study of the Asian Network for Surveillance of Resistant Pathogens (ANSORP). J Antimicrob Chemother. 2004;53:457–63. PMID:14963068, http://dx.doi.org/10.1093/jac/dkh118.View ArticlePubMedGoogle Scholar
- Hung IF, Tantawichien T, Tsai YH, Patil S, Zotomayor R. Regional epidemiology of invasive pneumococcal disease in Asian adults: epidemiology, disease burden, serotype distribution, and antimicrobial resistance patterns and prevention. Int J Infect Dis. 2013;17:e364–73. PMID:23416209, http://dx.doi.org/10.1016/j.ijid.2013.01.004.View ArticlePubMedGoogle Scholar
- Nathan JJ, Taib NM, Desa MNM, Masri SN, Yasin RM, Jamal F, Sagineedu SR, Karunanidhi A. Prevalence of macrolide resistance and in vitro activities of six antimicrobial agents against clinical isolates of Streptococcus pneumoniae from a multi-center surveillance in Malaysia. Med J Malaysia 2013;68(2):119–24.
- Felmingham D, Cantón R, Jenkins SG. Regional trends in beta-lactam, macrolide, fluoroquinolone and telithromycin resistance among Streptococcus pneumoniae isolates 2001–2004. J Infect. 2007;55:111–8. PMID:17568680, http://dx.doi.org/10.1016/j.jinf.2007.04.006.View ArticlePubMedGoogle Scholar
- Wolter N, von Gottberg A, du Plessis M, de Gouveia L, Klugman KP, Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa. Molecular basis and clonal nature of increasing pneumococcal macrolide resistance in South Africa, 2000–2005. Int J Antimicrob Agents. 2008;32:62–7. PMID:18339522, http://dx.doi.org/10.1016/j.ijantimicag.2008.01.013.View ArticlePubMedGoogle Scholar
- Imöhl M, Reinert RR, van der Linden M. Antibiotic susceptibility rates of invasive pneumococci before and after the introduction of pneumococcal conjugate vaccination in Germany. Int J Med Microbiol. 2015;305:776–83. PMID:26324014, http://dx.doi.org/10.1016/j.ijmm.2015.08.031.View ArticlePubMedGoogle Scholar
- Stephens DS, Zughaier SM, Whitney CG, Baughman WS, Barker L, Gay K, et al. Incidence of macrolide resistance in Streptococcus pneumoniae after introduction of the pneumococcal conjugate vaccine: population-based assessment. Lancet. 2005;365:855–63. PMID:15752529, http://dx.doi.org/10.1016/S0140-6736(05)71043–6.View ArticlePubMedGoogle Scholar
- Kaplan SL, Barson WJ, Lin PL, Romero JR, Bradley JS, Tan TQ, et al. Early trends for invasive pneumococcal infections in children after the introduction of the 13-valent pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2013;32:203–7. PMID:23558320, http://dx.doi.org/10.1097/INF.0b013e318275614b.View ArticlePubMedGoogle Scholar
- Dagan R, Juergens C, Trammel J, Patterson S, Greenberg D, Givon-Lavi N, et al. Efficacy of 13-valent pneumococcal conjugate vaccine (PCV13) versus that of 7-valent PCV (PCV7) against nasopharyngeal colonization of antibiotic-nonsusceptible Streptococcus pneumoniae. J Infect Dis. 2015;211:1144–53. PMID:25355940, http://dx.doi.org/10.1093/infdis/jiu576.View ArticlePubMedGoogle Scholar
- Camilli R, Daprai L, Cavrini F, Lombardo D, D’Ambrosio F, Del Grosso M, et al. Pneumococcal carriage in young children one year after introduction of the 13-valent conjugate vaccine in Italy. PLoS ONE. 2013;8:e76309. PMID:24124543, http://dx.doi.org/10.1371/journal.pone.0076309.View ArticlePubMedPubMed CentralGoogle Scholar
- Chiba N, Morozumi M, Shouji M, Wajima T, Iwata S, Ubukata K, et al. Changes in capsule and drug resistance of Pneumococci after introduction of PCV7, Japan, 2010–2013. Emerg Infect Dis. 2014;20:1132–9. PMID:24960150 http://dx.doi.org/10.3201/eid2007.131485.View ArticlePubMedPubMed CentralGoogle Scholar
- Amsden GW. Pneumococcal macrolide resistance--myth or reality? J Antimicrob Chemother. 1999;44:1–6. PMID:10459803, http://dx.doi.org/10.1093/jac/44.1.1.View ArticlePubMedGoogle Scholar
- Nuermberger E, Bishai WR. The clinical significance of macrolide-resistant Streptococcus pneumoniae: it’s all relative. Clin Infect Dis. 2004;38:99–103. PMID:14679455, http://dx.doi.org/10.1086/380126.View ArticlePubMedGoogle Scholar
- Lonks JR, Garau J, Gomez L, Xercavins M, Ochoa de Echagüen A, Gareen IF, et al. Failure of macrolide antibiotic treatment in patients with bacteremia due to erythromycin-resistant Streptococcus pneumoniae. Clin Infect Dis. 2002;35:556–64. PMID:12173129, http://dx.doi.org/10.1086/341978.View ArticlePubMedGoogle Scholar
- Zhanel GG, Wolter KD, Calciu C, Hogan P, Low DE, Weiss K, et al. Clinical cure rates in subjects treated with azithromycin for community-acquired respiratory tract infections caused by azithromycin-susceptible or azithromycin-resistant Streptococcus pneumoniae: analysis of Phase 3 clinical trial data. J Antimicrob Chemother. 2014;69:2835–40. PMID:24920652, http://dx.doi.org/10.1093/jac/dku207.View ArticlePubMedGoogle Scholar
- Morris PS, Gadil G, McCallum GB, Wilson CA, Smith-Vaughan HC, Torzillo P, et al. Single-dose azithromycin versus seven days of amoxycillin in the treatment of acute otitis media in Aboriginal children (AATAAC): a double blind, randomised controlled trial. Med J Aust. 2010;192:24–9. PMID:20047544.PubMedGoogle Scholar
- Southern KW, Barker PM, Solis-Moya A, Patel L. Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst Rev. 2012;11:CD002203. PMID:23152214.PubMedGoogle Scholar
- Valery PC, Morris PS, Byrnes CA, Grimwood K, Torzillo PJ, Bauert PA, et al. Long-term azithromycin for Indigenous children with non-cystic-fibrosis bronchiectasis or chronic suppurative lung disease (Bronchiectasis Intervention Study): a multicentre, double-blind, randomised controlled trial. Lancet Respir Med. 2013;1:610–20. PMID:24461664, http://dx.doi.org/10.1016/S2213-2600(13)70185–1.View ArticlePubMedGoogle Scholar
- Baddour LM, Yu VL, Klugman KP, Feldman C, Ortqvist A, Rello J, et al. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia. Am J Respir Crit Care Med. 2004;170:440–4. PMID:15184200 http://dx.doi.org/10.1164/rccm.200311-1578OC.View ArticlePubMedGoogle Scholar
- Nie W, Li B, Xiu Q. β-Lactam/macrolide dual therapy versus β-lactam monotherapy for the treatment of community-acquired pneumonia in adults: a systematic review and meta-analysis. J Antimicrob Chemother. 2014;69:1441–6. PMID:24535276 http://dx.doi.org/10.1093/jac/dku033.View ArticlePubMedGoogle Scholar
- Sligl WI, Asadi L, Eurich DT, Tjosvold L, Marrie TJ, Majumdar SR. Macrolides and mortality in critically ill patients with community-acquired pneumonia: a systematic review and meta-analysis. Crit Care Med. 2014;42:420–32. PMID:24158175 http://dx.doi.org/10.1097/CCM.0b013e3182a66b9b.View ArticlePubMedGoogle Scholar
- Cilloniz C, Albert RK, Liapikou A, Gabarrus A, Rangel E, Bello S, et al. The Effect of Macrolide Resistance on the Presentation and Outcome of Patients Hospitalized for Streptococcus pneumoniae Pneumonia. Am J Respir Crit Care Med. 2015;191:1265–72. PMID:25807239 http://dx.doi.org/10.1164/rccm.201502-0212OC.View ArticlePubMedGoogle Scholar
- Garin N, Genné D, Carballo S, Chuard C, Eich G, Hugli O, et al. β-Lactam monotherapy vs β-lactam-macrolide combination treatment in moderately severe community-acquired pneumonia: a randomized noninferiority trial. JAMA Intern Med. 2014;174:1894–901. PMID:25286173 http://dx.doi.org/10.1001/jamainternmed.2014.4887.View ArticlePubMedGoogle Scholar
- Postma DF, van Werkhoven CH, van Elden LJ, Thijsen SF, Hoepelman AI, Kluytmans JA, et al. Antibiotic treatment strategies for community-acquired pneumonia in adults. N Engl J Med. 2015;372:1312–23. PMID:25830421 http://dx.doi.org/10.1056/NEJMoa1406330.View ArticlePubMedGoogle Scholar